Indoles, nucleosides and their analogs are known in the art as having utility in the treatment of viral infections in mammals, including humans. Viruses that infect mammals and are treatable by the administration of pharmaceutical compositions comprising indoles, nucleosides or their analogues or derivatives include but are not limited to hepacivirus including HCV, human immunodeficiency virus (HIV), pestiviruses such as bovine viral diarrhea virus (BVDV), classic swine fever virus (CSFV, also known as hog cholera virus), and Border disease virus of sheep (BDV), and flaviviruses like dengue hemorrhagic fever virus (DHF or DENV), yellow fever virus (YFV), West Nile virus (WNV), shock syndrome and Japanese encephalitis virus (Moennig et al., Adv. Vir. Res. 1992, 41:53-98; Meyers, G. and Thiel, H-J., Adv. In Viral Res., 1996, 47:53-118; Moennig et al., Adv. Vir. Res. 1992, 41:53-98; S. B. Halstead, Rev. Infect. Dis., 1984, 6:251-64; S. B. Halstead, Science, 1988, 239:476-81; T. P. Monath, New Engl. J. Med., 1988, 319:641-3).
Indoles
Certain indole analogues and derivatives have been used to treat infection with human immunodeficiency virus (HIV).
For example, Williams et al. teaches substituted indoles for the treatment of HIV infection in U.S. Pat. No. 5,527,819 to Merck. The compounds disclosed in the '819 patent comprise a large class represented generically by the following broad structural Formula (III):
in which the variables X, Y, Z, R and R6 are broadly defined to embrace about one hundred compounds. In most examples shown, Y is SO2, Z is —C(O)NH2, and R an optionally substituted phenyl.
U.S. Pat. No. 5,124,327 to Greenlee et al. and assigned to Merck & Co. discloses a class of optionally substituted sulfonylphenyl indole compounds. These compounds are allegedly active as reverse transcriptase inhibitors and therefore useful in the treatment of HIV infection and AIDS.
U.S. Pat. No. 6,710,068 to Idenix Pharmaceuticals, Ltd., discloses a class of phenylindoles that are substituted with at least two moieties other than hydrogen on either the phenyl ring or the benzyl ring of the indole function, or on both rings. The substituents are generally contained at the 3″ and 5″ positions if located on phenyl ring, and at the 4′ and 5′; 5′ and 6′ or the 5′ and 7′ positions if located on the benzyl ring of the indole moiety. See also PCT Publication No. WO 02/083126.
PCT Publication No. WO 2004/014364 to Idenix Pharmaceuticals discloses yet another class of phenylindoles that display enhanced anti-HIV activity. Like their predecessors, these compounds are substituted with at least two moieties other than hydrogen on either the phenyl ring or the benzo ring of the indole functionality, or on both rings. In addition, these compounds incorporate a number of substituents having a carboxamide functionality at position-2 on the indole group of the compound, the position shown in Formula (III) above as “Z”.
Idenix Pharmaceuticals disclosed still another class of phenylindole compounds, these being phospho-phenylindoles, that are useful in the treatment of HIV and/or AIDS (US 2006/0074054 and WO 06/054182).
Bristol Myers Squibb is the assignee of numerous patents, published patent applications, and PCT publications that disclose various optionally substituted indoles, azaindoles, piperazines, and pyrrolidines for the treatment of HIV and/or AIDS. See U.S. Publication No. 2004/0006090 to Kadow et al.; U.S. Publication No. 2004/0063746 to Regueiro-Ren et al.; U.S. Publication No. 2003/0096825 to Wang et al.; U.S. Publication No. 2003/0236277 to Kadow et al.; and WO 03/068221 to Kadow et al.
WO 01/02388 to SmithKline Beecham S. P. A discloses optionally substituted phenylindoles with a carbamyl substituent that have utility in the treatment of HIV, AIDS, osteoporosis, cancers, and Alzheimer's disease.
Warner-Lambert Company discloses various indole-thiazepinones, oxazepinones, diazepinones, benzothiophenes, benzofurans, and indole-2-carboxamides for the treatment of HIV. (See U.S. Pat. No. 5,424,329 to Boschelli et al.; U.S. Pat. No. 5,565,446 to Boschelli et al.; U.S. Pat. No. 5,703,069 to Connor et al.; and WO 96/29077 to Warner-Lambert Company).
Shinogi & Co. disclose optionally substituted indole derivatives that are viral integrase inhibitors useful as anti-HIV drugs (U.S. Publication No. 2002/0019434 to Fujishita et al.; U.S. Pat. No. 6,716,605 to Fujishita et al.; and U.S. Pat. No. 6,506,787 to Fujishita et al.)
U.S. Pat. No. 5,945,440 to Kleinschroth et al. discloses a class of indolocarbazole amides for the treatment of a variety of diseases including cancer, viral diseases (including HIV), cardiac and vascular diseases, bronchopulmonary diseases, inflammatory disorders, degenerative diseases of the central nervous system, and other diseases.
Gunasekera et al. in U.S. Pat. No. 4,866,084 teaches certain bisindole alkaloid compounds that have antiviral and antitumor activity, including HSV (herpes simplex virus). U.S. Pat. No. 5,935,982 to Dykstra et al. reports a different class of bisindoles that have specific utility versus retroviral infections and especially HIV.
Matsunaga et al., in U.S. Pat. No. 5,852,011 (Dec. 22, 1998), discloses a class of indole derivatives substituted by a heteroaryl function and an amide function. The compounds are said generally to possess antitumor, antiviral, and antimicrobial properties.
Dykstra et al., in U.S. Pat. No. 5,935,982 discloses a class of bis-indoles and specifically propose their use for treating retroviral infections, and especially infection by HIV.
Domagala et al., in U.S. Pat. No. 5,929,114 (Jul. 27, 1999) discloses a class of arylthio and bithiobisarylamide compounds, including indole derivative, that reportedly have antibacterial and antiviral activity.
Pevear et al., in U.S. Pat. No. 5,830,894 (Nov. 3, 1998) discloses a class of triazinoindole derivatives that reportedly have anti-pestivirus activity, most notably BVDV activity.
Indoles have been used in the treatment of diseases other than HIV. U.S. Pat. No. 5,981,525 to Farina et al. discloses a complex array of indoles for use in the treatment of osteoporosis based on their ability to inhibit osteoclast H+-ATPase and thus reduce bone resorption. U.S. Pat. No. 6,025,390, also to Farina et al., teaches another group of indole derivatives, termed heteroaromatic pentadienoic acid derivatives that too are useful in the treatment of osteoporosis. U.S. Pat. No. 5,489,685 to Houpis et al. discloses a series of compounds that are furo(2,3-b) pyridine carboxylic acid esters, whose utility is in the treatment of HIV.
In light of the fact that HIV infections have reached epidemic levels worldwide and have tragic effects on the infected host, there remains a strong need to provide new and effective pharmaceutical agents to treat these viral infections with low toxicity to the host.
It is an object of the invention to provide compounds, methods of use, and compositions for the treatment of a host infected with HIV or for the treatment of AIDS related symptoms.